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WO1998052563A1 - REMEDES CONTRE LA DEMENCE DU TYPE ALZHEIMER CONTENANT DES DERIVES DE η-SULTAME - Google Patents

REMEDES CONTRE LA DEMENCE DU TYPE ALZHEIMER CONTENANT DES DERIVES DE η-SULTAME Download PDF

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Publication number
WO1998052563A1
WO1998052563A1 PCT/JP1998/002122 JP9802122W WO9852563A1 WO 1998052563 A1 WO1998052563 A1 WO 1998052563A1 JP 9802122 W JP9802122 W JP 9802122W WO 9852563 A1 WO9852563 A1 WO 9852563A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
dementia
hydrate
acceptable salt
compound
Prior art date
Application number
PCT/JP1998/002122
Other languages
English (en)
Japanese (ja)
Inventor
Tatsuro Yagami
Kei-Ichi Ueda
Original Assignee
Shionogi & Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shionogi & Co., Ltd. filed Critical Shionogi & Co., Ltd.
Priority to AU72371/98A priority Critical patent/AU7237198A/en
Publication of WO1998052563A1 publication Critical patent/WO1998052563A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles

Definitions

  • the present invention relates to an inhibitor for nerve cell death containing an r-sultam derivative, an inhibitor for nerve cell death caused by amiguchi j3 protein, and a therapeutic or preventive agent for Alzheimer's dementia.
  • Alzheimer's dementia which has become a major social problem, has recently attracted attention as a dementia with degeneration and loss of nerve cells, mainly seen in old age.
  • the development of drugs aimed at preventing and treating the disease has been actively pursued, but at this stage, the development of fundamental therapeutic drugs has not yet been achieved.
  • Alzheimer's dementia Accumulation of senile plaques and neurofibrillary tangles have been observed in the brain tissue of patients with Alzheimer's dementia, and these are cited as causes of the onset and progression of Alzheimer's dementia. Since amyloid / 3 protein deposits are observed in senile plaques, it is presumed that Alzheimer's dementia is mainly caused by amyloid i3 protein deposition, aggregation and senile plaque formation.
  • Alzheimer's dementia only two drugs are approved for the treatment of Alzheimer's dementia: evening culin (tetrahydroaminoacridine) and alicebut (donebecil hydrochloride).
  • These drugs called acetylcholinesterase inhibitors, are based on the choline theory of reducing acetylcholine content in the brain of dementia with Alzheimer's type 1. It is a remedy.
  • acetylcholinesterase inhibitors are based on the choline theory of reducing acetylcholine content in the brain of dementia with Alzheimer's type 1. It is a remedy.
  • there are several possible mechanisms of Alzheimer's dementia and development of therapeutic agents other than acetylcholinesterase inhibitors is desired. Disclosure of the invention
  • the present inventors have intensively studied to develop a therapeutic or prophylactic agent for Alzheimer's dementia, and as a result, have found that asaltam derivatives represented by the following general formula (I) or pharmaceutically acceptable salts or The inventors have found that these hydrates have an inhibitory effect on nerve cell death caused by the amyloid 3 protein, and have completed the present invention.
  • FIG. 1 is a graph showing the effect of amyloid 3 protein on neuronal cell death.
  • the present invention relates to an inhibitor of nerve cell death caused by an amyloid protein containing an asaltam derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof or a hydrate thereof, and a therapeutic or preventive agent for Alzheimer's type 1 dementia.
  • an agent Specifically, the effect of amyloid / 3 protein on neuronal cell death was tested, and its inhibitory effect was confirmed.
  • the cerebral cortex or hippocampus is removed and suspended in an isotonic solution. Then, the protease alone or the DNAse is added, and the mixture is kept at 20:40 (preferably at 25 ° C to 38) for 5 to 20 minutes (preferably, 10 minutes to 10 minutes). Culture for 15 minutes to disperse the nerve cells.
  • the nerve cells Suspend the nerve cells in the medium and spread them on a culture plate coated to prevent adsorption.
  • isotonic solution for example, salts such as sodium chloride, potassium chloride, sodium phosphate, and potassium phosphate, and sugars such as glucose and sucrose may be used as a mixture.
  • Proteases include, for example, trypsin, chymotrypsin, collagenase, thrombin, plasmin, eras, and papain (0.4). -mg / m 1) and the like, preferably using trypsin.
  • a DNA degrading enzyme for example, deoxyliponuclease I and II are used, and preferably, deoxyribonuclease I is used.
  • Leivbovitz's L-15 medium use Leivbovitz's L-15 medium, Eagle's Basic medium, Eagle's MEM medium, F10 medium, Dulbecco's MEM medium, RPI-16401 medium, F12 medium, Iscove's MDM medium, McCoy's 5a, etc.
  • a coating agent for the plate poly-L-lysin, collagen, polyethyleneimine, polyorditin and the like are used.
  • amyloid i3 protein (1 M to 10 M, preferably 2) alone, or (ii) amyloid / 3 protein (lM to 10 / i M, preferably Is added 2M) and the compound of the present invention (0.1M to 10M, preferably 1M).
  • MTT 3- (4,5-dimethylthiazol-2-yl) —2,5-diphenyltetrazolium bromide is added to neuronal cells.
  • MTT 3- (4,5-dimethylthiazol-2-yl) —2,5-diphenyltetrazolium bromide is added to neuronal cells.
  • 20 ° C to 40 ° C (preferably at 25 to 38) for 30 minutes to 180 minutes (preferably 60 minutes to 120 minutes).
  • the MTT assay is an assay that measures the mitochondrial respiratory capacity of a cell, and a decrease in the measured value means cell death.
  • the present invention relates to an inhibitor for nerve cell death, in particular, an inhibitor for nerve cell death caused by amyloid 3 protein, in particular, a neurodegenerative disease such as Alheimer's type 1 dementia, Parkinson's disease, Cerebellar degenerative agents, Wilson's disease, Down's syndrome, Retinitis pigmentosa, Lewy body disease, Cerebral ischemia, Amyotrophic lateral sclerosis, Prion-related diseases, Kreuzfeld-Jakob disease, Kr disease, Multiple sclerosis Syndrome, hereditary ataxia, Shy-Dorega syndrome, progressive supranuclear syndrome, Huntington's chorea, spinal muscular atrophy, Reye syndrome, status epilepticus, progressive multifocal white matter brain, viral Encephalitis, normobaric hydrocephalus, subacute sclerosing panencephalitis, degeneration after cerebral spinal cord injury, A therapeutic or prophylactic agent for frontal lobe dementia, gray myelitis, glaucoma, autonom
  • “Lower alkyl” means a C1-C8 linear or branched alkyl group, and specifically, methyl, ethyl, n-propyl, i-propyl, n-butyl, i_butyl , S-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, s-pentyl, t-pentyl, n-hexyl, neohexyl, i-hexyl, s-hexyl, t-hexyl , N-heptyl, n-octyl and the like. Particularly, methyl and ethyl are preferable.
  • “Lower alkoxy” means a linear or branched C 1 -C 8 alkyloxy, specifically, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy S-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, neopentyloxy, s-pentyloxy, t-pentyloxy, n-hexyloxy, neohexyloxy, i-hexyloxy, s-hexyloxy , T_hexyloxy and the like. Particularly, methoxy is preferred.
  • Cycloalkyl means a C3-C7 cyclic alkyl, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Particularly, cyclopropyl is preferred.
  • Aryl means unsubstituted or substituted phenyl or naphthyl.
  • substituents include a halogen, a lower alkoxy, a lower alkyl, and a nitro group.
  • the substituent may have one or more substituents, and is bonded at any substitutable position.
  • Arylalkoxy means a group in which the above-mentioned lower alkoxy group is substituted by the above-mentioned aryl group, and is benzyloxy, 4-chlorobenzyloxy, 4-methoxybenzilyoxy, 3,4-dichlorobenzylo.
  • Xy, 3,4-dimethoxybenzyloxy, 4-nitrobenzyloxy, 2-phenylethyloxy, 2- (4-chlorophenyl) ethyloxy, 2- (4-methoxyphenyl) ethyloxy examples thereof include 1-naphthylmethyloxy and 2-naphthylmethyloxy. Particularly, 41-methoxybenzyloxy is preferable.
  • Heteroaryl refers to a 5- to 10-membered member containing at least one arbitrarily selected oxygen atom, sulfur atom and / or nitrogen atom in a ring, and optionally condensed with a carbon ring or another hetero ring. And forms a bond at any position.
  • pyridyl eg, 2-pyridyl
  • thiazolyl eg, 4-thiazolyl
  • isothiazolyl eg, 5-isothiazolyl
  • oxazolyl eg, 2-oxazolyl
  • isoxazolyl eg, 4-isoxazolyl
  • imidazolyl for example, 1-imidazolyl
  • triazolyl for example, 4-triazolyl
  • indole for example, 1-indole
  • benzothiazolyl for example, 2-benzothiazolyl
  • Heteroarylalkoxy means a group in which the above-mentioned alkoxy group is substituted by the above-mentioned heteroaryl group, and is 2-pyridylmethyloxy, 3-pyridylmethyloxy, 4-pyridylmethyloxy, 2-imidazolylmethylo. Xy, 4-imidazolylmethyloxy, 2-thiazolylmethyloxy, 4-thiazolylmethyloxy and the like.
  • “Lower alkylcarbonyl” means a group in which a lower alkyl group is substituted on a carbonyl group, and examples thereof include acetyl, propionyl, butyryl, valeroyl, hexanol, heptanyl, and octanoyl.
  • Aryl-capillon refers to a group in which a carbonyl group is substituted with a carbonyl group. Means benzoyl, 4-chlorobenzyl, 4-methoxybenzoyl, 212 tolbenzyl, 3,4-dichlorobenzyl, 3,4-dimethoxybenzoyl, 3,4-dinitrobenzoyl, 1-naphthoyl , 2-naphthyl, etc. are shown.
  • substituted rubamoyl examples include N-methylcarbamoyl, N, N-dimethylcarbamoyl, N-hydroxycarbamoyl, and N-methyl-N-hydroxyxycarbamoyl. No.
  • “Lower alkoxycarbonyl” means a group in which a carbonyl group is substituted by the above-mentioned alkoxy group, and examples thereof include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, and isobutoxycarbonyl.
  • Substituted amino in “substituted or unsubstituted amino” means mono- or di-substituted amino, and examples of the substituent include lower alkyl and lower alkoxy. For example, methylamino, ethylamino, dimethylamino, methylethylamino and the like can be mentioned.
  • the compounds of the present invention also include pharmaceutically acceptable salts and hydrates.
  • Pharmaceutically acceptable salts include, for example, salts of alkali metals (eg, lithium, sodium, potassium), alkaline earth metals (eg, calcium, magnesium), ammonium or organic bases (eg, tritylamine, pyridine), and amino acids. No. Salts and hydrates can be formed by conventional methods.
  • compound (I) described in the present specification can be administered orally or parenterally.
  • compound (I) is used in the form of conventional preparations, for example, solid preparations such as tablets, powders, granules and capsules; liquid preparations; oily suspensions; or liquid preparations such as syrups or elixirs. It can be used as any dosage form.
  • compound (I) should be used as an aqueous or oily suspension for injection or external application Can be.
  • any of conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, etc. can be used, and other additives, for example, preservatives And a stabilizer.
  • the dose of compound (I) will vary depending on the method of administration, the age, weight, condition and type of disease of the patient, but is usually 10 to 500 mg orally per day for adults. Preferably, 50 to; 100 mg, or parenterally, 1 to 250 mg, preferably 5 to 10 mg per day, which may be administered in 1 to 5 divided doses.
  • HMPA Hexamethylphosphoramide
  • the compound represented by the formula (I) can be synthesized according to Japanese Patent Application Laid-Open No. 6-218189.
  • N-Butyllithium n-hexane solution (1.6 M, 69.5 ml, 11 1 mm o) in ice-cooled diisopropylamine (15.5 ml, 10.6 mm o 1) 1) is added dropwise over 20 minutes with stirring, and after the addition is completed, the mixture is further stirred for 15 minutes.
  • the reaction solution was cooled to 178 ° C, THF lOOml was added, and the N-ethyl-1,2-isothiazolidine-11,1-dioxide 3 (15 g, 1) obtained in the step (1) was added.
  • 00. 5 mm o 1) 3,5_di-tert-butyl-1-4- (methoxymethoxy) benzaldehyde
  • the cerebral cortex was extracted from a Sprague-Dawley rat (embryonic day 19), and an isotonic solution (137 mM sodium chloride, 5.4 mM potassium chloride, 0. It was suspended in 17 mM disodium phosphate, 0.22 mM potassium phosphate, 5.5 mM glucose, 59 mM sucrose; 25 ml each). Trypsin and deoxyliponulase were added at 4 mg / ml and 0.4 mg / nil, respectively, and cultured at 37 ° C for 12 minutes to disperse neurons.
  • Nerve cells were suspended in Leivbovitz's L-15 medium (containing 5% calf serum + 5% horse serum) at a concentration of 1 ⁇ 10 6 cells / ml. Nerve cells were seeded at a density of 2.5 ⁇ 10 5 cells / cm 2 on a culture plate coated with poly-L-sin. Neurons, 37: in cultured at 5% C0 2 incubator, was used in the experiment on the second day.
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof or a hydrate thereof has an inhibitory effect on amyloid / 3 protein-induced neuronal cell death, and is useful for Alhaima type 1 dementia. It can be expected as a medicine.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés représentés par la formule générale (I), des sels pharmaceutiquement acceptables de ces composés ou des hydrates de ceux-ci. Etant donné qu'ils ont un effet inhibiteur en ce qui concerne la mort des cellules nerveuses due à la protéine β-amyloïde, ces composés sont considérés comme étant utiles en tant que remèdes contre la démence du type Alzheimer.
PCT/JP1998/002122 1997-05-21 1998-05-14 REMEDES CONTRE LA DEMENCE DU TYPE ALZHEIMER CONTENANT DES DERIVES DE η-SULTAME WO1998052563A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU72371/98A AU7237198A (en) 1997-05-21 1998-05-14 Remedies for dementia of alzheimer type containing gamma-sultam derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP13131997 1997-05-21
JP9/131319 1997-05-21

Publications (1)

Publication Number Publication Date
WO1998052563A1 true WO1998052563A1 (fr) 1998-11-26

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1026162A4 (fr) * 1997-10-24 2001-01-17 Shionogi & Co Agent anti-rhumatismal
JP2007516939A (ja) * 2003-06-23 2007-06-28 ニューロケム （インターナショナル） リミテッド アミロイド関連疾患を治療するための方法および組成物

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06211819A (ja) * 1992-10-28 1994-08-02 Shionogi & Co Ltd ベンジリデン誘導体
WO1995017154A2 (fr) * 1993-12-23 1995-06-29 Andrulis Pharmaceuticals Corporation Utilsation de thalidomide pour le traitement de troubles neurocognitifs
JPH07215854A (ja) * 1993-12-21 1995-08-15 Eli Lilly & Co アルツハイマー病の抑制法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06211819A (ja) * 1992-10-28 1994-08-02 Shionogi & Co Ltd ベンジリデン誘導体
JPH07215854A (ja) * 1993-12-21 1995-08-15 Eli Lilly & Co アルツハイマー病の抑制法
WO1995017154A2 (fr) * 1993-12-23 1995-06-29 Andrulis Pharmaceuticals Corporation Utilsation de thalidomide pour le traitement de troubles neurocognitifs

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HIRAI S.: "DEUF THERAPY OF ALZHEIMER'S DISEASE.", STRIDES OF MEDICINE, XX, JP, vol. 174., no. 06., 5 August 1995 (1995-08-05), JP, pages 632 - 636., XP002917259 *
MCGEER P. L., ET AL.: "ANTI-INFLAMMATORY DRUGS IN THE FIGHT AGAINST ALZHEIMER'S DISEASE.", ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, NEW YORK ACADEMY OF SCIENCES., US, vol. 777., 1 January 1996 (1996-01-01), US, pages 213 - 220., XP002917261, ISSN: 0077-8923, DOI: 10.1111/j.1749-6632.1996.tb34421.x *
SCHNABEL J.: "NEW ALZHEIMER'S THERAPY SUGGESTED.", SCIENCE, AMERICAN ASSOCIATION FOR THE ADVANCEMENT OF SCIENCE, US, vol. 260., 18 June 1993 (1993-06-18), US, pages 1719/1720., XP002917260, ISSN: 0036-8075, DOI: 10.1126/science.8323582 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1026162A4 (fr) * 1997-10-24 2001-01-17 Shionogi & Co Agent anti-rhumatismal
US6525081B1 (en) 1997-10-24 2003-02-25 Shionogi & Co., Ltd. Antirheumatic
US6743923B2 (en) 1997-10-24 2004-06-01 Shionogi & Co., Ltd. Antirheumatic agent
JP2007516939A (ja) * 2003-06-23 2007-06-28 ニューロケム （インターナショナル） リミテッド アミロイド関連疾患を治療するための方法および組成物
JP2007516938A (ja) * 2003-06-23 2007-06-28 ニューロケム （インターナショナル） リミテッド アミロイド関連疾患を治療するための方法および組成物

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